This invention relates to the production of pyridyl ketones from corresponding substituted pyridines containing at least one alkyl or aralkyl substituent joined to a carbon of the pyridine nucleus by a methylene radical of such substituent, by oxidation of the pyridine in liquid phase with air or other oxygen-containing gas, to convert the methylene radical to a carbonyl radical.
The pyridyl ketones produced by the present invention are in general known compounds which have previously been produced by chemical oxidation, as with potassium permanganate, or by condensation reactions such as the Claisen condensation. Such prior methods of production are relatively laborious and expensive, and the present invention provides an improved method for producing these ketones.
It has previously been proposed to oxidize lower alkyl-substituted pyridines to corresponding pyridine carboxylic acids with oxygen or air in the presence of a catalyst or oxidizing reagent. In general, these proposals use different reagents and reaction conditions and produce acids instead of the pyridyl ketones produced by the present invention.
Hanotier-Bridoux U.S. Pat. No. 3,833,599 is directed to oxidation of alkyl pyridines to corresponding carboxy pyridines, but in its Example 5 reports that oxidation of 4-ethylpyridine produced 79% of isonicotinic acid and 21% of 4-acetyl pyridine. The process requires large proportions of carboxylic acid as solvent and of a cobaltic salt of an alkanoic acid as catalyst-reagent, and requires chemical separation of the product mixture. In contrast, the present invention cleanly produces the ketone as the substantially exclusive reaction product, free of carboxy acids, and permits product recovery by simple fractionation.
Godin U.S. Pat. No. 3,075,989 reports the oxidation of 2-methyl-5-ethylpyridine to 2-methyl-5 -acetylpyridine with molecular oxygen and an organic peroxide or hydroperoxide in a process which for adequate yields requires periodic additions of peroxide over a reaction period ranging up to 24 hours or more. In contrast, the present invention uses inorganic catalysts and produces equivalent or better yields in a fraction of the time.
The pyridyl ketones produced by the present invention have various valuable uses, such as intermediates in the manufacture of pharmaceutical and agricultural products and of plastic polymers, as inhibitors, etc. For example: acetylpyridines are useful as non-complexing compounds for brightening in galvanic zinc baths (German Offen. No. 1,919,305; French Demande No. 2,015,422), and to inhibit the reaction of trichloroethane on aluminum (U.S. Pat. No. 3,444,248); 2-acetylpyridine is used to make the antihistamine doxylamine succinate (JACS 71, 887, 1949); 2-methyl-5 -acetylpyridine is reported useful as an intermediate in the preparation of plastics polymers (U.S. Pat. No. 3,075,989); and 2-benzoylpyridine is useful to improve the ultraviolet light stability of high density polyethylene (Canadian Pat. No. 836,635).
In accordance with the invention, the substituted pyridine used as a starting material has at least one substituent which is either a lower alkyl group having from 2 to 8 carbon atoms or an aralkyl group, especially an aryl-methylene group such as phenylmethylene or napthylmethylene, and which is connected to a carbon of the pyridine nucleus through a methylene radical of such group. The pyridine may contain more than one such substituent, for example, as in 2,5-diethylpyridine. It may contain other hydrocarbon substituents, such as an alkyl group which is not joined to the nucleus by an oxidizable methylene radical, for example, the methyl substituent in 2-methyl-5 -ethylpyridine. The pyridine may also contain other substituents which do not interfere with the desired oxidation, as for example a chloro or nitro substituent on another carbon of the nucleus.
The starting material may be represented as a compound of the formula: ##SPC1##
in which
R represents an alkyl group of from 1 to 7 carbon atoms, or an aryl group, PA1 R.sub.1 represents a lower alkyl group or hydrogen or a non-oxidizable inorganic substituent such as --NO.sub.2 --SO.sub.3 H, or halogen, PA1 n is an integer of 1 to 5, and PA1 m is zero or an integer of 1 to 4. PA1 1. Manganese compounds, especially manganese dioxide (MnO.sub.2) PA1 2. chromium compounds, especially sodium and potassium dicromates (Na.sub.2 Cr.sub.2 O.sub.7 and K.sub.2 Cr.sub.2 O.sub.7) PA1 3. vanadium compounds, especially vanadium pentoxide (V.sub.2 O.sub.5)
The substituted pyridine starting material is subjected to oxidizing reaction conditions at elevated temperatures and under sufficient pressure to maintain liquid phase conditions. The reaction mixture preferably does not contain a solvent as such, and especially not a carboxylic acid solvent such as acetic acid, but may desirably contain a minor amount of vapor pressure additive. A catalyst is desirably present, although with some pyridines and under some conditions, reaction will occur without an added catalyst, especially with 2- and 4-substituted pyridines. The desired oxidation reaction is produced by causing intimate mixing of air or other oxygen-containing gas with the liquid phase reaction mixture containing the pyridine starting material and the catalyst, if present, and such mixing is continued until oxygen uptake has ceased or substantially ceased, as indicated by tests of the gas outflow. The airflow is then stopped and the reaction mixture cooled.
The pyridyl ketone formed in the reaction mixture is conveniently recovered by fractional distillation. Such distillation usually also yields a quantity of the unreacted pyridine starting material which can be reused in subsequent reactions, and may yield more or less of a tarry residue. While a batch process is described, it will be understood that the invention is also unable in a continuous process.
The reaction may be carried out in a closed vessel adapted to be heated and pressurized, fitted with an inlet and an outlet for oxidizing gas, and with a stirring device. We have carried out the process both in glass equipment and in stainless steel equipment.
The temperature of the reaction mixture should be high enough to produce the desired oxidation reaction. Higher temperatures increase the rate of oxidation and yield of desired product, but excessive temperatures may cause destructive oxidation of the materials present and produce increased amounts of tarry residue. The optimum temperature or temperature range to be used will depend on the catalyst used, on the pressure, and on the particular pyridine being oxidized. In general, we have found it convenient to use a temperature of about 200.degree. C. in investigative runs, and have found that temperature to produce effective results, but variations therefrom may be found best for particular operations. For 2-benzyl- and 4-benzyl-pyridines, we consider that the temperature should be at least about 100.degree. C. Alkyl pyridines generally require higher minimum temperatures for reaction, not less than about 170.degree. C. Higher temperatures may be used in any case, and the maximum is in part a matter of convenience but also to avoid degradation of the reactants. In general, we prefer to use temperatures up to about 300.degree. C.
The pressure in the reaction chamber should be sufficient to maintain liquid phase conditions at the prevailing temperature. Higher pressures increase the solubility and concentration of the oxidizing gas in the liquid phase reaction mixture and hence increase the rate of reaction. The pressure to be used varies with the temperature and with the particularly pyridine being oxidized. 2-benzyl- and 4-benzyl-pyridines which have boiling points of 276.degree. and 287.degree. C., respectively, will oxidize at atmospheric pressure at 200.degree. C., but higher pressures are desirably used. Alkyl pyridines require elevated pressures, i.e., above atmospheric pressure. With them we prefer to use a pressure of at least about 150 psig. The maximum pressure used is largely a matter of convenience and safety, and depends on the equipment being used and on the desired rate of reaction. Pressures may range upward to 1000 psig or higher, but in general we prefer to use pressures not more than about 1000 psig. With the foregoing guide lines, the person skilled in the art can readily determine the temperature and pressure to be used in any particular application.
The reaction mixture is desirably composed substantially entirely of the substituted pyridine to be oxidized, and a solvent or diluent is desirably not used. In particular, the reaction mixture desirably does not contain a carboxylic acid as a solvent or otherwise, since such acids react with other components and interfere with clean fractionation to recover the desired reaction product. The mixture may, however, contain a small proportion of a vapor pressure additive, such as water or benzene, which has a lower boiling point than the pyridine, and which is inert and not reactive under the reaction conditions. The amount of such additive will depend on the operating conditions, especially the temperature and pressure being used. The presence of such vapor pressure additive facilitates the use of higher reaction pressures, and is especially advantageous to enhance safety of operation by changing the vapor mixture in the reaction vessel to one outside an explosive range. The amount of additive should not be so great as to significantly dilute the pyridine, and preferably is in the range from none up to about 10% of the amount of pyridine used.
The oxidizing gas used is most conveniently air, but other oxygen-containing gases or gas mixtures may be used, such as air fortified with extra oxygen or diluted with nitrogen or other inert gas. Any such mixture desirably contains only a minor proportion of oxygen, say from about 10% to about 30% oxygen. As with other operating conditions, the optimum oxygen content of the oxidizing gas will vary with other conditions of the reaction and with the particular pyridine being oxidized. Some compounds will undergo the desired reaction with, and withstand, stronger oxidizing conditions than others, while others will give good yields and cleaner results with milder conditions. In general, we prefer to use only sufficiently strong oxidizing conditions as will give satisfactory yields of the desired ketones, and thus to avoid further oxidation as to carboxylic acids and to minimize danger of degradative reactions.
The presence of a catalyst is usually preferred and is in some cases essential. With 2-benzyl- and 4-benzyl-pyridines the desired oxidation reaction was carried out with useful yields in the absence of a catalyst and at atmospheric pressure in glass equipment. With 2-ethyl- and 4-ethylpyridines, the desired oxidation reaction was carried out with good yields in the absence of a catalyst. With such ethylpyridines, the reaction was carried out at elevated pressure and in stainless steel equipment composed of an alloy identified as AISI 316.
A wide variety of catalysts have been found operative. Different catalysts produce different results with the same starting material, and the same catalyst will produce different results with different starting materials, operating conditions, etc.
Catalysts which may be used for the process of the present invention are in general known inorganic oxidation catalysts or reagents. The useful catalysts include the "heavy metals" and their oxides, hydrated oxides, and inorganic salts. The heavy metals are designated as such in the Periodic Table given on page 632 of Hackh's Chemical Dictionary (Third Edition, 1944, The Blakiston Company, Philadelphia, PA) and include the metals having atomic numbers from 22 (titanium) to 92 (uranium) and falling in Periods IV to VII and in Groups 1b, 2b, 3a, 4a, 4b, 5b, 6b, 7b, and 8 of the Periodic Table of Elements as set forth in the CRC Handbook of Chemistry and Physics, 50th Ed., 1969.
Such heavy metals which may be used, either as such or as oxides or hydrated oxides or inorganic salts thereof, include specifically the metals vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, molybdenum, palladium, tin, tungsten, platinum, mercury, and uranium.
Other elements which are useful in the same forms as the heavy metals are magnesium, arsenic, and selenium. Still other materials which have been found useful as catalysts comprise sulphur and ammonium bromide.
By inorganic salts we mean to include compounds in which the metal appears in the anion thereof, as in alkali metal salts of chromic or dichromic acid, e.g., Na.sub.2 Cr.sub.2 O.sub.7, and also compounds in which the metal appears in the cation thereof, as in nickel sulfate. By hydrated oxides, we mean to include compounds which under reaction conditions may lose a molecule of water to form an oxide as for example tungstic acid (H.sub.2 WO.sub.4) which may be considered a hydrated form of tungstic oxide (WO.sub.3).
The preferred catalysts, which have been found widely useful under various conditions and are readily available commercially comprise:
The amount of catalyst used can vary over a wide range, and depends on the particular catalyst used, the pyridine being oxidized, and the reaction conditions. If too little is used, yields will be low or non-existent. On the other hand, too much catalyst can cause excessive oxidation and degradation of the starting compound and the desired product, so that the reaction product will be a useless tarry mixture. In any event, the amount used is a "catalytic amount" as distinguished from a chemically "equivalent amount" and is very much smaller than a chemically equivalent amount. Useful amounts may be as little as 0.01% by weight of the amount of pyridine being treated and may be as much as 5% by weight of the pyridine.
The following Examples show different applications and variations of the process. They are given for purposes of illustration only and are not intended to limit the scope of the invention.